Placebo Solution Research Articles

Tantum verde mouthwash for tonsillectomy: A prospective, double-blind, randomized control trial

ObjectivesPost-tonsillectomy pain control is still considered a challenge. Topical agents would seem to be an ideal, safe option. Our objective was to compare the efficacy of mouthwash preparation with anti-inflammatory, anesthetic, and analgesic properties (Tantum Verde®, 0.15% benzydamine hydrochloride) with that of placebo in improving post-tonsillectomy morbidity. MethodsA prospective, double blind, randomized clinical trial was performed. Patients older than 12-years-of-age who underwent tonsillectomy were recruited. Participants were randomized into 2 groups to receive either 0.15% benzydamine hydrochloride (TV) mouthwash solution (study arm) or a placebo solution. They were instructed to gargle the intervention they received 3 times a day for 7 days following surgery. Primary outcomes were intensity and duration of post-operative pain (using VAS visual analogue score) during a 2-week follow-up period. Secondary outcomes were pain medication demand, readmission, incidence of post-operative bleeding, hospital stay duration, and time to resume normal solid diet. ResultsThirty-nine patients completed the study, of whom 23 received TV and 16 received placebo. The mean age was 23.1 years. There was no significant difference between the groups in the primary or secondary outcomes. ConclusionsThe data suggest that topical treatment with TV mouthwash solution was not found to be superior to placebo in the management of post-tonsillectomy pain, bleeding, and return to a regular solid diet. Further research studies should be designed to investigate the ideal treatment for reducing post-tonsillectomy morbidity. Clinical trial registrationNIH identifier: NCT02190762; IRB NHR002814.

Cyclosporin A ameliorates cerebral oxidative metabolism and infarct size in the endothelin-1 rat model of transient cerebral ischaemia

Cerebral microdialysis can be used to detect mitochondrial dysfunction, a potential target of neuroprotective treatment. Cyclosporin A (CsA) is a mitochondrial stabiliser that in a recent clinical stroke trial showed protective potential in patients with successful recanalisation. To investigate specific metabolic effects of CsA during reperfusion, and hypothesising that microdialysis values can be used as a proxy outcome measure, we assessed the temporal patterns of cerebral energy substrates related to oxidative metabolism in a model of transient focal ischaemia. Transient ischaemia was induced by intracerebral microinjection of endothelin-1 (150 pmol/15 µL) through stereotaxically implanted guide cannulas in awake, freely moving rats. This was immediately followed by an intravenous injection of CsA (NeuroSTAT; 15 mg/kg) or placebo solution during continuous microdialysis monitoring. After reperfusion, the lactate/pyruvate ratio (LPR) was significantly lower in the CsA group vs placebo (n = 17, 60.6 ± 24.3%, p = 0.013). Total and striatal infarct volumes (mm3) were reduced in the treatment group (n = 31, 61.8 ± 6.0 vs 80.6 ± 6.7, p = 0.047 and 29.9 ± 3.5 vs 41.5 ± 3.9, p = 0.033). CsA treatment thus ameliorated cerebral reperfusion metabolism and infarct size. Cerebral microdialysis may be useful in evaluating putative neuroprotectants in ischaemic stroke.

THE EFFECT OF BCAA ON ISOMETRIC FORCE FOLLOWING ENDURANCE EXERCISE IN A HOT ENVIRONMENT

ABSTRACT Introduction: Fatigue due to endurance exercise results from both peripheral and central changes, and may influence subsequent performance during a strength task. The increase in serotonin concentration is one of the central factors associated with endurance exercise-induced fatigue, particularly in hot environments. A nutritional strategy employed to reduce serotonergic activation is supplementation with branched-chain amino acids (BCAA). Objective: To investigate whether BCAA supplementation attenuates the reduction in isometric force caused by prior endurance exercise in a hot environment. Methods: Nine volunteers (aged 25.4 ± 1.2 years) performed a 2-min maximal voluntary isometric contraction (MVCISO) of upper limb muscles before and after an endurance exercise on a cycle ergometer at 40% of the maximal aerobic power. The volunteers underwent three experimental trials: 1) endurance exercise in a temperate environment (23°C and 60% RH); exercise in a hot environment (35°C and 60% RH) with the ingestion of: 2) a placebo solution or 3) a solution containing BCAA 30 mg.kg−1. During the MVCISO test, the isometric force of flexor muscles of the right elbow, core body temperature (TCORE) and heart rate (HR) were measured. Results: Isometric force decreased following endurance exercise in the hot environment, and BCAA administration did not attenuate this reduction. Greater TCORE and HR values were observed following endurance exercise in the heat, compared to pre-exercise values, and supplementation did not interfere with these physiological responses. Conclusion: The reduction in isometric force, caused by previous endurance exercise in a hot environment, was not diminished by supplementation with BCAA. Level of evidence I; Type of study: Therapeutic studies - Investigation of treatment outcomes.

Assessment of selenium supplementation by systemic injection at birth on pre-weaning calf health

The objective of this randomized clinical trial was to evaluate the effect of selenium and vitamin E supplementation by systemic injection on dairy calf health and growth during the pre-weaning period. The study was conducted at 39 dairy farms in Ontario, selected through a convenience sample of farms in close proximity to either Guelph or Kemptville. A total of 835 Holstein heifer calves were enrolled in this study. At birth, calves were randomly allocated to receive selenium and vitamin E supplementation by injection (3 mg sodium selenite and 136 IU dl-a-tocopherol acetate) or a placebo solution. At enrollment, producers recorded time of birth, calving ease, and colostrum feeding status. At weekly visits to the individual dairy farms, trained technicians collected measurements and samples from enrolled calves. Blood was collected from calves that were up to 8 d of age to assess the concentration of serum total protein and selenium. Between 8 and 15 d of age, fecal samples were collected to identify the presence of rotavirus and Cryptosporidium parvum (C. parvum) using a commercially +available lateral immuno-chromatography antigen detection kit. Each enrolled calf was also weighed and assessed for health scores during the first, second, and seventh weeks of life. The average serum selenium concentration (SD) in treated calves was 0.08 μg/mL (0.02), versus 0.06 μg/mL (0.01) in control calves. The incidence of failure of passive transfer (FPT) among study calves was 21%, and did not differ between treatment groups. The mean average daily gain (ADG) for the study period was 1.43 lb (0.65 kg)/day and was not associated with selenium and vitamin E supplement injection. Of the 761 fecal samples tested, 272 (36%) and 118 (16%) tested positive for C. parvum and rotavirus antigen, respectively. Selenium and vitamin E treatment had a protective effect against rotavirus infection. However, there was no effect of experimental treatment on C. parvum infection status. Reduced odds of treatment for diarrhea was also seen in the selenium and vitamin E treatment group. This study suggests that selenium and vitamin E injection at birth could improve pre-weaning health by reducing rotavirus infection and diarrhea.

Evaluating the Effects of Oral and Topical Simvastatin in the Treatment of Acne Vulgaris: A Double-blind, Randomized, Placebo-controlled Clinical Trial.

Acne vulgaris is a common dermatologic disorder which results in psychological consequences. Inflammatory responses play an important role in the development of inflammatory acne lesions. Recently, many studies have demonstrated anti-inflammatory effects of statins; thus, the aim of this study was to evaluate the efficacy of oral and topical Simvastatin as adjunct therapy in the treatment of acne vulgaris. A total of 76 patients with moderate to very severe acne vulgaris, all receiving oral azithromycin (250 mg, 3 times a week, orally) and topical benzoyl peroxide gel (5%, once daily) were assigned to three groups: 1) Oral group received 20mg/day of oral simvastatin and blank solution, 2) Topical group received simvastatin 1% topical solution and oral placebo, 3) Placebo group received oral placebo and blank solution. The severity of acne was determined by global acne grading system (GAGS) at baseline and after 8 weeks of treatment. Comparing the three groups showed that topical simvastatin was associated with greater decrease in acne severity as compared with those of oral and placebo groups. Moreover, the oral simvastatin appeared to be more efficacious as compared with placebo group (P value<0.001). Oral and topical simvastatin were well tolerated in almost all patients. Although preliminary, the results of this study showed that oral and topical statins, drugs with anti-inflammatory properties, can be considered as effective treatment for acne vulgaris as an adjunct to standard treatment. However, further studies with larger sample size, using improved formulations of topical simvastatin are needed to confirm these results.

Evaluation of the effects of erythropoietin and interleukin-6 in rats submitted to acute spinal cord injury

OBJECTIVE:To evaluate the effects of interleukin-6 (IL-6) and erythropoietin (EPO) in experimental acute spinal cord injury (SCI) in rats.METHODS:Using standardized equipment, namely, a New York University (NYU) Impactor, a SCI was produced in 50 Wistar rats using a 10-g weight drop from a 12.5-mm height. The rats were divided into the following 5 groups of 10 animals each: “Group EPO”, treated with erythropoietin only; “Group EPO + IL-6”, treated with both substances; “Group IL-6”, receiving IL-6 administration only; “Group Placebo”, receiving a placebo solution; and “Group Sham”, submitted to an incomplete procedure (only laminectomy, without SCI). All drugs and the placebo solution were administered intraperitoneally for three weeks. The animals were followed up for 42 days. Functional motor recovery was monitored by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35 and 42. Motor-evoked potential tests were performed on the 42nd day. Histological analysis was performed after euthanasia.RESULTS:The group receiving EPO exhibited superior functional motor results on the BBB scale. IL-6 administration alone was not superior to the placebo treatment, and the IL-6 combination with EPO yielded worse results than did EPO alone.CONCLUSIONS:Using EPO after acute SCI in rats yielded benefits in functional recovery. The combination of EPO and IL-6 showed benefits, but with inferior results compared to those of isolated EPO; moreover, isolated use of IL-6 resulted in no benefit.

Postoperative Analgesic Efficacy of Sub-Tenon's Block with Levobupivacaine in Retinal Surgery under General Anesthesia.

Background:Vitreoretinal surgery is associated with undesirable intraoperative and postoperative complications including pain, postoperative nausea and vomiting, and oculocardiac reflex (OCR). Systemic analgesics have side effects and are contraindicated in some cases. We hypothesized that the preoperative sub-Tenon's injection of levobupivacaine with general anesthesia would decrease postoperative pain and intraocular pressure as well as the incidence of complication.Methods:Eighty patients who were presented for vitreoretinal surgery, aged 30–60 years, were enrolled in the study. General anesthesia was administrated to all patients; then, they were randomized into two equal groups (40 each) – Group I: patients received 5 mL placebo solution for sub-Tenon's block and Group II: patients received 4 mL levobupivacaine 0.5% in 1 mL saline for sub-Tenon's block. Postoperative pain was evaluated using a verbal pain scale. Surgeon satisfaction, postoperative analgesic consumption, and perioperative hemodynamics were also reported.Results:Verbal rating pain scores were significantly lower at the first 6 h postoperative in Group II (sub-Tenon's levobupivacaine) compared to Group I (sub-Tenon's placebo). First analgesic rescue time and total dose of analgesic consumption were significantly reduced in Group II compared to Group I. There was a lower incidence of OCR with sub-Tenon's levobupivacaine (Group II), also surgeon satisfaction was significantly superior in the same group.Conclusion:The combination of general anesthesia with sub-Tenon's block using levobupivacaine in retinal surgery patients reduces pain scores after surgery; total analgesia requirement also decreases the incidence of OCR.

Efficacy of chlorhexidine rinses after periodontal or implant surgery: a systematic review.

Biofilm management and infection control are essential after periodontal and implant surgery. In this context, chlorhexidine (CHX) mouth-rinses are frequently recommended post-surgically. Despite its common use and many studies in this field, a systematic evaluation of the benefits after periodontal or implant surgery is-surprisingly-still missing. To evaluate the benefits of chlorhexidine rinsing after periodontal or implant surgery in terms of plaque and inflammation reduction potential. Furthermore, to screen whether the concentration changes or additives in CHX solutions reduce side effects associated with its use. A systematic literature search was performed for clinical trials, which compared CHX rinsing after periodontal or implant surgery with rinsing using placebo, non-staining formulations, or solutions with reduced concentrations of the active compound. Four databases (Medline, PubMed, Embase, Cochrane) were searched up to June 2018. Two reviewers independently identified and screened the literature. From 691 titles identified, only eleven publications met the inclusion criteria and were finally included. Mainly early publications assessed the benefits of CHX over placebo rinsing, whereas more recent publications focused more on the evaluation of new formulations with regard to effectiveness and side effects. The use of CHX after surgery showed in general significant reduction in plaque (means of 29-86% after 1week) and bleeding (up to 73%) as compared to placebo. No consensus, however, was found regarding the most beneficial CHX formulation avoiding side effects. Chlorhexidine rinsing helps to reduce biofilm formation and gingival inflammation after surgery. However, no additional reduction of periodontal probing depth over any given placebo or control solution could be found irrespective of whether CHX was used or not. The use of additives such as antidiscoloration systems (ADS) or herbal extracts may reduce side effects while retaining efficacy. Within the limitations of this review, it can be concluded that CHX may represent a valuable chemo-preventive tool immediately after surgery, during the time period in which oral hygiene capacity is compromised. To reduce the side effects of CHX and maintain comparable clinical effects, rinsing with less concentrated formulations (e.g., 0.12%) showed the most promising results so far.

AbobotulinumtoxinA: A New Therapy for Hip Osteoarthritis. A Prospective Randomized Double-Blind Multicenter Study.

Hip Osteoarthritis (OA) causes pain and disability. Here we evaluate abobotulinumtoxinA (Dysport®) (AboBoNT-A) injections versus placebo as a novel treatment option to improve hip range of motion, pain and quality of life. This prospective randomized double-blind multicenter study (EudraCT # 2012-004890-25) recruited 46 outpatients with hip OA who were randomized 2:1 to the Treatment Group (TG; 31 subjects), or the Placebo Group (PG; 15 subjects). The TG received 400 U of AboBoNT-A injected into the adductor muscles, and the PG received placebo solution. The primary endpoints were the difference in Harris Hip Score (HHS) and Visual Analogic Scale for pain (VAS) at Week 4 between groups (TG vs. PG). Secondary endpoints were the change from baseline in HHS, VAS pain, Medical Research Council scale for muscle strength (MRC) and Short Form scale (SF-36) scores. In TG at Week 4, the HHS and VAS score were significantly improved compared to PG, and pairwise assessments showed significant improvements in HSS and VAS pain at each time point compared to baseline for TG. No significant changes were observed in MRC and SF-36 over time, though SF-36 showed a positive trend. There were no significant differences from baseline in the PG. No adverse events were detected in either treatment group. AboBoNT-A injections in hip OA improve range of motion and pain without any significant side effects.

MECHANISM OF ANTIVIRAL ACTION AND EVALUATION OF THE EFFICACY OF THE NEW PREPARATION FORTEPREN&lt;sup&gt;®&lt;/sup&gt; IN THE COMPLEX THERAPY OF CHRONIC RECURRENT HERPESVIRUS INFECTION OF GENITAL LOCALIZATION

Aim. The study of the mechanism of antiviral action and evaluation of the clinical efficacy, safety and tolerability of therapy with Fortepren® in patients with chronic recurrent herpesvirus infection of genital localization (CRHVI). Materials and methods. Clinical studies were carried out of a drug Fortepren® (0.4% sodium polyprenyl phosphate solution), which was administered to patients who underwent a basic therapeutic course of the drug Acyclovir-Acry® to relieve the acute phase of the disease. The study was performed on 80 male and female patients selected during the screening with a confirmed diagnosis of CRHVI. Two groups were formed. Patients of group 1 (experimental) were intramuscularly injected with Fortepren® at a dose of 2 ml (8 mg) three times at intervals of 21 days by 3 ± 2, 24 ± 2 and 45 ± 2 days following the 10-day basic course of treatment of the acute phase of diseases with the use of the acyclovir tablets of 400 mg - 13 ± 2, 34 ± 2 and 55 ± 2 days from the beginning of the study. Patients of the 2nd group (control) were intramuscularly injected with placebo solution at a volume of 2 ml instead of Fortepren®. To evaluate Fortepren® efficacy, the following criteria were used: increase in the duration of the inter-recessive period, a decrease in the frequency of relapses over the entire observation period; decrease in the severity of relapses, estimated in points, changes in immunological parameters according to the dynamics of changes in the production of the main cytokines. Results. In patients treated with Fortepren®, the inter-recurrence period for the entire study period increased statistically from 29.36 ± 2.16 to 42.98 ± 3.29 days, while in the control group this indicator have not changed. Accordingly, in patients treated with Fortepren®, a statistically significant reduction in the incidence of recurrence of CRHVI from 3.03 ± 0.02 before treatment to 1.94 ± 0.19 was observed during treatment in the absence of a decrease in the frequency of relapses in the control. Evaluation of the severity of CRHVI relapses in patients treated with Fortepren® indicates the efficacy of this protocol. The sum of the scores of the mean values of CRHVI symptoms signs was statistically significantly decreased in the group 1 from 7.36 ± 0.35 points at the 1 st visit before the start of treatment to 4.75 ± 0.35 points during the treatment. No changes were seen in the control group. The level of leukocyte virus-induced interferon (LVI-IFN) in the patients of the group 1 increased from 36% to 64% in the end of the clinical trial compared to the control group, in which the increase in LVI-IFN titers was not observed. To further justify the possibility of increasing the immune response of cells, establishing possible mechanisms that determine the efficacy of treatment for CRHVI with Fortepren®, evaluation of the production of IFNz, IFNy, IL-10, IL-12p40, IL-12p70, IL-15, IL-2, IL-4, MIF-Fz, TNFа was made. In the of the study levels of all these cytokines was increased in patients treated with Fortepren® compared with the control group. Conclusion. The efficacy of using Fortepren® in a dose of 2 ml (8 mg) with intramuscular administration to patients with chronic recurrent herpesviral infection of genital localization at the stage of remission three times with an interval of 21 days by 3 ± 2, 24 ± 2 and 45 ± 2 days after the end of 10 day basic course of treatment of the acute phase of the disease with the use of the drug acyclovir.

Preoperative Tranexamic Acid for Treatment of Bleeding, Edema, and Ecchymosis in Patients Undergoing Rhinoplasty

Evidence has emerged on the efficacy of tranexamic acid to control blood loss and postoperative complications after rhinoplasty. To investigate the results of tranexamic acid use to reduce intraoperative bleeding, postoperative eyelid edema, and periorbital ecchymosis in rhinoplasty. For this systematic review of randomized clinical trials, searches were performed in PubMed, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, Science Direct, Google Scholar, OpenThesis, and ClinicalTrials.gov from inception to December 23, 2017. Key words included tranexamic acid, rhinoplasty, and nasal surgical procedures. The following elements were used to define eligibility criteria: (1) population: patients undergoing rhinoplasty surgery; (2) intervention and controls: tranexamic acid vs placebo solution or no-treatment control group; (3) outcomes: intraoperative bleeding, postoperative eyelid edema and periorbital ecchymosis, and thromboembolic events; and (4) study type: randomized clinical trials. Two reviewers extracted data and assessed study quality according to the Cochrane guidelines for randomized clinical trials. Treatment effects were defined as weighted mean difference (WMD) and 95% CIs. The strength of evidence was analyzed using the Grading of Recommendations Assessment, Development, and Evaluation rating system. Intraoperative bleeding, postoperative eyelid edema and periorbital ecchymosis. To calculate the effect sizes, means and SDs were obtained for each study group and outcome of interest. Five studies comprising 276 patients were included in the systematic review: 177 patients (64.1%) were women, and mean age was 26.8 (range, 16-42) years. Four studies comprising 246 patients estimated the amount in intraoperative bleeding as a primary outcome and were included in the meta-analysis. Eyelid edema and ecchymosis were evaluated as outcomes in 2 studies. Tranexamic acid was associated with reduced bleeding during rhinoplasty was found (WMD, -42.28 mL; 95% CI, -70.36 to -14.21 mL), with differences (P = .01) between oral (WMD, -61.70 mL; 95% CI, -83.02 to -40.39 mL; I2 = 0%) and intravenous (WMD, -23.88 mL; 95% CI, -45.19 to -2.58 mL; I2 = 56%) administration. Eyelid edema and ecchymosis scores in patients receiving tranexamic acid were significantly lower compared with the control group within the first postoperative week: lower eyelid edema, WMD, -0.76; 95% CI, -1.04 to -0.49 and lower eyelid ecchymosis, WMD, -0.94; 95% CI, -1.80 to -0.08. No cases of thromboembolic events were reported. Current available evidence suggests that preoperative administration of tranexamic acid is safe and may reduce intraoperative bleeding as well as postoperative eyelid edema and ecchymosis in patients undergoing rhinoplasty.

Effects of Topical Phenytoin Cream on Episiotomy Repair in Primiparous Women: A Double Blind Clinical Trial.

Episiotomy is the most prevalent obstetrical procedure with the purpose of either widening vaginal outlet or helping the fetus to deliver as soon as possible with the most feto-maternal safety. The aim of this study is to find out the effects of topical phenytoin cream on wound repair in primiparous women. One-hundred-thirty primiparous mothers were referred to Kowsar Hospital in Qazvin province participated in this clinical trial. Sixty-five participants were assigned in each of intervention and control groups. The intervention group was treated with topical 1% Phenytoin cream and 10% povidone-iodine (betadine) solution and the control group received placebo and betadine solution. Wound irrigation with betadine was performed as the routine order in the hospital, three times daily and two centimeters of topical phenytoin or placebo cream, were applied to the wound twice daily. The rate of episiotomy repair was measured by REEDA index in the first 24 h, the fifth and the tenth puerperal day. Data analyses were done t-test and chi-square test and Mann-Whitney. In the first 24 h, it was 6.43 ± 2.15 in the intervention group versus 6.52 ± 5.09 in the control group with no significant difference. However on The 5th day, it appeared 4.56 ± 3.01 in the intervention group versus 6.54 ± 2.98 in the control group (p < 0.001), likewise it was 5.82 ± 2.83 in the control group on the tenth day (p < 0.001). Significant difference was detected both in the 5th and 10th postpartum days. The result of this trial suggested that 1% phenytoin cream speeds-up the wound healing process; therefore it could be applied for accelerating episiotomy repair.

Effects of castration and a lidocaine-plus-flunixin treatment on growth and indicators of pain, inflammation, and liver function in Korean cattle bull calves

The aim of this study was to determine the effects of castration and a lidocaine-plus-flunixin (LF) treatment on growth and indicators of pain, inflammation, and liver function in Korean cattle bull calves. Forty Korean cattle bull calves (body weight 197.0 ± 2.94 kg and age 6.3 ± 0.09 months) were each assigned to one of four treatments (n = 10 heads/group): no castration with no LF injection (NC-NLF); no castration with LF injection (NC-LF); castration with no LF injection (C-NLF); and castration with LF injection (C-LF). LF treatment included a local anesthetic lidocaine hydrochloride injection (12 mL of 2% in the scrotum) and intravenous injection of a non-steroidal anti-inflammatory drug, flunixin meglumine (2 mg/kg body weight of 50 mg/mL solution), immediately prior to castration. For the NLF groups, a 0.9% NaCl placebo solution was used. Castration was performed surgically using a Newberry knife and a Henderson castrating tool. Blood was collected immediately before castration and at h 0.5, h 6, d 1, d 3, d 7, and d 14 after castration. Feed intake was recorded daily, and body weight was measured on the day prior to the experiment and at d 14 after castration. Castration tended (P = 0.07) to decrease average daily weight gain, but LF treatment did not affect weight gain. Castration increased both circulating cortisol concentrations (P < 0.001) at h 0.5 after castration and substance P (SP) concentrations (P = 0.001) at h 6 after castration. However, the LF treatment did not significantly reduce cortisol and SP concentrations in castrated animals. Castration increased (P < 0.001) circulating haptoglobin (Hp) concentrations on d 1 and d 3 after castration, and LF treatment tended (P = 0.09) to decrease Hp concentrations on d 1 and decreased (P = 0.02) Hp concentrations on d 3. Castration did not affect glutamic oxaloacetic transaminase (GOT) and glutamic pyruvate transaminase (GPT) concentrations. LF treatment increased GOT concentrations at h 6 (P < 0.001), d 1 (P < 0.001), and d 3 (P = 0.003). LF treatment also increased GPT concentrations on d 1 (P = 0.006) and d 3 (P = 0.003). In conclusion, castration of bull calves resulted in time-sequential increases in circulating concentrations of cortisol at h 0.5, SP at h 6, and Hp on d 1. LF treatment did not significantly reduce elevated cortisol and SP, but tended to decrease elevated Hp concentrations in castrated animals. Our study demonstrates that LF treatment is not sufficient for the reduction of the indicators of pain and inflammation in castrated calves, suggesting that additional alleviation methods are required.

Extemporaneous preparation strategy for early phase clinical studies

Extemporaneous preparations (EPs) of investigational drugs, which are compounded at the clinical study site by a pharmacist, are being increasingly used in early phase clinical studies to accelerate the development of new medicines. The successful application of EP strategies in clinical studies requires ‘fit-for-purpose’ formulation design and preparation processes, as well as administration procedures that are safe, flexible, cost-effective, and simple to adapt by a compounding pharmacist at the clinical site. DNS-7801 is a weakly basic investigational compound that exhibits a higher aqueous solubility at lower pH with its solubility dropping off precipitously with increase in pH. This phenomenon is known to result in potential risk of variable and decreased exposure in vivo. Combination of citrate buffer at pH 3.0 and hydroxypropylbetadex enabled formulation of DNS-7801 solutions that were stable as formulated and up on manipulation for oral administration. The solutions were compatible with apple juice, used to mask (blind) the potential taste differences between the placebo and DNS-7801 solutions when dosing study subjects. The oral administration of the solutions resulted in dose proportional Cmax, AUC0-24, and AUC0–∞ of DNS-7801 in non-elderly and elderly subjects. A key advantage of the use of an EP approach with DNS-7801 was the flexibility in dose selection that this approach offered because DNS-7801 concentration in the preparation and/or volume could be readily adjusted based on real-time cohort data.

Oral Magnesium Supplementation and Metabolic Syndrome: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

The objective of the study was to evaluate the efficacy of oral magnesium supplementation in the improvement of metabolic syndrome (MetS) and its components. This is a randomized double-blind, placebo-controlled clinical trial that enrolled 198 individuals with MetS and hypomagnesemia who were randomly allocated to receive either 30mL of magnesium chloride 5% solution, equivalent to 382mg of elemental magnesium (n=100), or placebo solution (n=98), daily for 16 weeks. Serum magnesium levels <1.8mg/dL defined hypomagnesemia. At final conditions, a total of 48 (48%) and 76 (77.5%) individuals had MetS in the magnesium and placebo groups (P=0.01), respectively. At baseline, percent of individuals with 3, 4, and 5 criteria of MetS in the magnesium group were 60.0%, 37.0%, and 3.0%, respectively, and in the control group 55.1%, 35.7%, and 9.2%, respectively. Between basal and final conditions, changes in the components of MetS were significantly higher in the magnesium than placebo groups: -3.6±3.3mmHg, P=0.001 for systolic blood pressure; -5.5±1.7mmHg, P=0.005 for diastolic blood pressure; -12.4±3.6mg/dL, P<0.005 for fasting glucose; -61.2±24mg/dL, P=0.003 for triglycerides; and 0.9±0.4mg/dL, P=0.06 for high-density lipoprotein cholesterol. Magnesium supplementation improves MetS by reducing blood pressure, hyperglycemia, and hypertriglyceridemia.

Effects Of A Caffeine-carbohydrate Mouth Rinsing On Sprinting Kinetics And Kinematics In Fasted Athletes

Carbohydrate mouth rinsing during an intermittent fasting has been reported to be advantageous for endurance performance; however, there appears to be no clear effect on repeated sprints. What has not been investigated previously is the effects of combined caffeine and carbohydrate (CAF-CHO) mouth rinsing on speed-endurance performance commonly performed by track and field athletes during a fasted state. PURPOSE: To determine the influence of CAF-CHO mouth rinsing on sprinting kinetics and kinematics, as well as subjective exertion during a speed-endurance bout performed in a fasted state. METHOD: In a counterbalanced, single-blind random order design, eleven (n = 11) well-trained National level male sprinters and middle-distance runners performed three 15-sec all-out sprints on a Woodway nonmotorized force treadmill, interspersed with 2-min active recovery between sprints. Athletes rinsed 25 ml of CAF-CHO (4g carbohydrate, 5 mg caffeine), or a similarly coloured placebo solution (PLA) prior to warm-up (30-min pre-trial), 1-min pre-trial, and the mid-way of each period of active recovery. On one occasion, no mouth rinse (NMR) was administered. The study was conducted within the second and third quarters of Ramadan, and each session separated by at least 72 hours. RESULTS: At the start of each trial, the rating of perceived exertions (RPE), readiness to train, blood glucose, and lactate concentrations were similar (p > 0.05). A significant primary effect of trial (3 x 15 seconds sprint) was observed for the distance (p = 0.019), revealing a longer average distance achieved in the CAF-CHO compared to PLA trial (69.80 + 3.57 vs. 68.08 + 3.22; p = 0.026; EF: 0.5), and NMR (69.69 + 3.82; p = 0.680; EF: 0.2). The difference between NMR and PLA also approached significance (p = 0.073; ES: 0.5). The CAF-CHO intervention also obtained better results in all other sprint measures such as average velocity, peak acceleration, and peak horizontal force, although these differences were not significant. Post-trial RPE was higher during NMR (7.23 + 1.92) as compared to CAF-CHO (6.54 + 2.15) and PLA (6.38 + 1.94) (p = 0.247). CONCLUSION: In challenging metabolic conditions, CAF-CHO mouth rinsing might have potential to improve measures of sprint training performance with a positive ergogenic effect on speed endurance performance.

Evaluating the Effect of Resveratrol on the Healing of Extraction Sockets in Cyclosporine A–Treated Rats

The objective of this study was to investigate the effects of resveratrol on alveolar socket healing after tooth extraction in normal and cyclosporin A (CsA)-treated rats. Seventy-two female Sprague-Dawley rats were separated into 4 groups of 18. Group 1 was injected with a placebo solution intraperitoneally. Group 2 was injected with resveratrol (10μmol/kg) intraperitoneally. Groups 3 and 4 were injected with CsA (10mg/kg) subcutaneously for 8days once daily before tooth extraction. Next, the teeth were extracted and CsA injection continued until the animals were sacrificed. Eight days after commencing the CsA injections, group 4 was injected with resveratrol while continuing with CsA injections. Nine rats from each group were sacrificed on days 14 and 28, and sections were examined to assess the degree of inflammation, formation of connective tissue, and new bone formation. Immunohistochemical analysis was used to evaluate the alveolar socket healing process using osteocalcin and osteopontin markers. A P value less than .05 was considered significant. There was more new bone formation in group 2 than in the other 3 groups on day 14 after tooth extraction (P<.05), and there was more new bone formation in group 2 than in groups 3 and 4 on day 28 after extraction (P<.05). Based on the immunohistochemical assessment, the amount of osteocalcin and osteopontin labeling was greater in group 2 compared with the other 3 groups on day 14 (P<.05); however, on day 28 after extraction, it was greater in group 4 compared with group 3 (P<.05). Resveratrol improves alveolar socket healing in normal and CsA-treated rats. Resveratrol also increases levels of osteocalcin and osteopontin in normal and CsA-treated rats. These results suggest that this natural compound is useful for alveolar socket healing after tooth extraction.

Changes in feeding, social, and lying behaviors in dairy cows with metritis following treatment with a nonsteroidal anti-inflammatory drug as adjunctive treatment to an antimicrobial

Dairy cows with metritis display sickness behaviors, and nonsteroidal anti-inflammatory drugs (NSAID) have the potential to reduce these responses. The objective of this study was to investigate changes in feeding, social, and lying behaviors in dairy cows with metritis that had been treated with the NSAID meloxicam. After parturition, cows were housed in a dynamic, mixed-parity group of 20 animals with access to 12 electronic feed bins, 2 electronic water bins, and 24 lying stalls in a freestall pen. Every third day after parturition, vaginal discharge was evaluated to diagnose metritis based on the presence of foul smell and characteristic visual appearance. When diagnosed with metritis, animals (n = 87) were randomly allocated to receive either a single dose of meloxicam (0.5 mg/kg of body weight subcutaneously) or a placebo solution. All metritic animals received an antimicrobial (ceftiofur) for 5 d. We measured feeding and social behaviors at the feed bunk, as well as lying behaviors, and assessed within-cow changes from the day before to the day of (d 0) NSAID treatment, and from the day before to d 1 to 5 after treatment. Generally, behaviors changed around the day of diagnosis of metritis. Compared with the placebo group, cows that received meloxicam had a greater increase in the number of visits to the feeder, but tended to show less of an increase in dry matter intake and feeding time. These differences did not persist beyond 24 h after NSAID treatment. We observed no differences in changes in number of meals and feeding rate on d 0, but from d 1 to 5 cows treated with meloxicam had a lesser decrease in the number of meals and tended to have a greater decrease in feeding rate than did placebo-treated cows. In multiparous cows on d 0 and from d 1 to 5, meloxicam treatment was associated with decreased lying times. In primiparous cows, lying time changes were similar between treatments on d 0, but lying times increased more on d 1 to 5 for meloxicam than for placebo cows. Overall, cows changed the number of lying bouts on d 0, and this increase tended to be smaller for the meloxicam cows. There were no treatment differences in changes of social behavior. In summary, we observed inconsistent and generally small effects of a single dose of meloxicam in addition to antimicrobial therapy on the behavior of cows with metritis.

Post-Exercise Carbohydrate-Energy Replacement Attenuates Insulin Sensitivity and Glucose Tolerance the Following Morning in Healthy Adults.

The carbohydrate deficit induced by exercise is thought to play a key role in increased post-exercise insulin action. However, the effects of replacing carbohydrate utilized during exercise on postprandial glycaemia and insulin sensitivity are yet to be determined. This study therefore isolated the extent to which the insulin-sensitizing effects of exercise are dependent on the carbohydrate deficit induced by exercise, relative to other exercise-mediated mechanisms. Fourteen healthy adults performed a 90-min run at 70% max starting at 1600–1700 h before ingesting either a non-caloric artificially-sweetened placebo solution (CHO-DEFICIT) or a 15% carbohydrate solution (CHO-REPLACE; 221.4 ± 59.3 g maltodextrin) to precisely replace the measured quantity of carbohydrate oxidized during exercise. The alternate treatment was then applied one week later in a randomized, placebo-controlled, and double-blinded crossover design. A standardized low-carbohydrate evening meal was consumed in both trials before overnight recovery ahead of a two-hour oral glucose tolerance test (OGTT) the following morning to assess glycemic and insulinemic responses to feeding. Compared to the CHO-DEFICIT condition, CHO-REPLACE increased the incremental area under the plasma glucose curve by a mean difference of 68 mmol·L−1 (95% CI: 4 to 132 mmol·L−1; p = 0.040) and decreased the Matsuda insulin sensitivity index by a mean difference of −2 au (95% CI: −1 to −3 au; p = 0.001). This is the first study to demonstrate that post-exercise feeding to replaceme the carbohydrate expended during exercise can attenuate glucose tolerance and insulin sensitivity the following morning. The mechanism through which exercise improves insulin sensitivity is therefore (at least in part) dependent on carbohydrate availability and so the day-to-day metabolic health benefits of exercise might be best attained by maintaining a carbohydrate deficit overnight.

Impact of carbohydrate mouth rinsing on time to exhaustion during Ramadan: A randomized controlled trial in Jordanian men

Mouth rinsing using a carbohydrate (CHO) solution has been suggested to improve physical performance in fasting participants. This study examined the effects of CHO mouth rinsing during Ramadan fasting on running time to exhaustion and on peak treadmill speed (Vpeak). In a counterbalanced crossover design, 18 sub-elite male runners (Age: 21 ± 2 years, Weight: 68.1 ± 5.7 kg, VO2max: 55.4 ± 4.8 ml/kg/min) who observed Ramadan completed a familiarization trial and three experimental trials. The three trials included rinsing and expectorating a 25 mL bolus of either a 7.5% sucrose solution (CHO), a flavour and taste matched placebo solution (PLA) for 10 s, or no rinse (CON). The treatments were performed prior to an incremental treadmill test to exhaustion. Three-day dietary and exercise records were obtained on two occasions and analysed. Anthropometric characteristics were obtained and recorded for all participants. A main effect for mouth rinse on peak velocity (Vpeak) (CHO: 17.6 ± 1.5 km/h; PLA: 17.1 ± 1.4 km/h; CON: 16.7 ± 1.2 km/h; P < .001, ηp2 = 0.49) and time to exhaustion (CHO: 1282.0 ± 121.3 s; PLA: 1258.1 ± 113.4 s; CON: 1228.7 ± 98.5 s; P = .002, ηp2 = 0.41) was detected, with CHO significantly higher than PLA (P < .05) and CON (P < .05). Oxygen consumption, heart rate, respiratory exchange ratio, and rating of perceived exertion were not significantly different between treatments or trials (P > .05). Energy availability from dietary analysis, body weight, and fat-free mass did not change during the last two weeks of Ramadan (P > .05). This study concludes that carbohydrate mouth rinsing improves running time to exhaustion and peak treadmill speed under Ramadan fasting conditions.